Henri Rochefort (physician)

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Henri Rochefort

Henri Rochefort is a French biochemical doctor, born on 20 November 1935 in Paris, who studied the influence of various hormones and their antagonists on breast and ovarian cancers. He is a corresponding member of the French Academy of sciences.

Biography[edit]

Training[edit]

He was born on 20 November 1935 in Paris to Fernande Bernhart, a decorator and Marcel Rochefort, a photographer.

After secondary studies in Paris (lycée Carnot) where he became a laureate of the Concours Général des lycées en Sciences Naturelles, he followed a university education with a doctorate in medicine in 1968, a licence ès sciences in 1965, a doctorat ès sciences 3e cycle endocrinologie- in 1966, then a doctorat ès sciences in 1972.

He was a medical intern in the Paris hospitals in the 1961 competition in clinical endocrinology departments and trained in research as an associate and then as a research fellow in Étienne-Émile Baulieu's Inserm Unit from 1964 to 1970.

Career[edit]

He was recruited at the Faculty of Medicine of Montpellier as Associate Professor, Hospital Biologist in 1970, then Professor of Biochemistry in 1981, then as Professor of Cell Biology from 1984 to 2004, and finally Professor Emeritus since 2005.

At the hospital as a Hospital Biologist, (1970-2001) he developed assays for steroid hormones, hormone receptors and prognostic and predictive tissue markers for response to targeted therapies in breast cancer. He continues his research as founding director of Unit 148 of the Inserm Cellular and Molecular Endocrinology Unit and then Hormones and Cancers Unit (1970-2000).

He is married and has 3 children.

Main scientific contributions[edit]

Henri Rochefort's scientific work has focused on the influence of sex steroid hormones and their antagonists in breast and ovarian cancer.

1. Pharmacology of sex steroid receptors. Some androgens are estrogenic when they interact with estrogen receptors (ER) (1-3). As early as 1972, Henri Rochefort showed that antiestrogens inhibit tumor growth via ERs, which then facilitated their routine use in the treatment of positive ER breast cancers. Discovery of a metabolite with a high affinity for RE, 4-hydroxytamoxifen, which is produced in vivo and accumulated in RE positive cancers. A mutation of the enzyme activating tamoxifen by hydroxylation is responsible for some innate tamoxifen resistance in patients treated for breast cancer. Antiestrogens also inhibit the effect of growth factors in the absence of estrogens. RU 486, a progesterone antagonist, inhibits the growth of breast cancer via the progesterone receptor, suggesting the value of anti-progestins for the treatment of antiestrogen-resistant breast cancers expressing this receptor.

2. By specifying the mechanism of estrogen mitogenic action in breast cancer lines, Henri Rochefort and his team discovered cathepsin D (cathe D) as an actor in tumor progression.  (17-33) As early as 1980, H. Rochefort with F Vignon introduced the notion of autocrine regulation by mitogenic factors secreted and induced by estrogens.[1][2] He focused the activity of his research unit on a 52 kilo-dalton glycoprotein, induced by estrogens and growth factors; secreted in excess by breast cancer cells and endowed with autocrine mitogenic activity.[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] With monoclonal antibodies, developed with Sanofi, an assay of 52 K protein in breast cancer extracts in several retrospective double-blind studies showed in a totally unexpected way that high concentrations of this protein in the primary tumor predicted the subsequent development of clinical metastases (an example of serendipity).[7][8][9]

The 52k protein was then identified as the precursor of cathepsin D (cathept D) a lysosomal protease diverted into the extracellular matrix.[5][6]

Henri Rochefort has clarified the mechanism of its transcriptional regulation by estrogens and its deregulation in breast cancers leading to its secretion.[11][12][13][14][15] Pro cath D acts, depending on the pH of the extracellular tumor medium, as a protease or as the ligand of a membrane receptor to facilitate the survival and growth of micro-metastases that have escaped from the tumor before its removal. After confirmation in many Centres around the world, Cathedral D has become the first example of a protease, the measurement of which in the primary tumor has a prognostic value.[6][13] Its overexpression after transfection of the D-cath gene into tumor cells increases their metastatic power in athymic mice. Conversely, the inhibition of its production by transfection of anti-sense RNA into breast cancer cells inhibits their growth and metastatic power in these mice. (29-32) Thus, cath D is a potential therapeutic target for breast cancers, mainly triple-negative cancers[18] as well as other solid tumors that overexpress it, such as colorectal cancer and melanoma.[6][13]

3. Other novel pathways have been opened, such as transcriptional interference between RE and transcriptional factors (AP1),[19] and variations in tissue expression by immunohistochemistry of ovarian hormone receptors (including estrogen beta receptor) in pre-cancerous breast lesions. Fibulin 1, induced by estrogens, is secreted in excess by ovarian cancer cells and accumulated in vivo in the extracellular matrix.[20][21] Progestogen-induced fatty acid synthase (also a potential therapeutic target.[22][23][24][25] Its early overexpression may partly explain the increase in breast cancer incidence by progestins in women treated for menopause.

Hypersensitivity to estrogens in "at risk" breast lesions may be due to a decrease in the estrogen beta receptor.[26]

In total, starting from fundamental research on human breast cancer lines and after having prepared original specific molecular probes, H. Rochefort has transferred some of his results to the clinic and contributed internationally to the understanding of the mechanisms of hormonal carcinogenesis and to the therapeutic management of breast and ovarian cancers.

4. Since 2000, as Professor Emeritus of Cell Biology and Member of the National Academies of Medicine and Science,

As research was no longer funded in France after retirement, Henri Rochefort reoriented himself towards general topics more directly useful in public health by leading several working groups.

  • Reports to the National Academy of Medicine on the Prevention of Breast and Ovarian Cancer.[27][28][29][30][31][32][33]
  • Activities at the Academy of Sciences: Organizer of the conference debate in plenary session: "Estrogens, health and environment" (2000).[34][35]

Henri Rochefort also participated in the creation of the Institut de Cancérologie de Montpellier (IRCM) by transferring the Inserm Hormones and Cancer Unit, and is currently a volunteer consultant in this Institute to facilitate transfer research, close to clinical oncologists.

5. Main books

1989 - Les Antiœstrogènes, with T. Maudelonde, Flammarion, Médecine-Sciences, Paris.[36]

2006 - Hormonal Control of Cell Cycle, in collaboration with S. Mehmed, P. Chanson, Y. Christen. Springer (Heidelberg).[37]

2008 - Hormonal Carcinogenesis V co Publisher with J Li. (Springer- New York) Proceeding of the Vth international symposium in La Grande Motte France. (pj flyer 2005)

2018 - H Rochefort: Hormones et Cancers du sein: Des mécanismes aux thérapies ciblées et à la Prévention. (European University Publishing, Berlin)[38]

Henri Rochefort is the author of numerous scientific articles[39][40]

Functions and distinctions[edit]

National[edit]

  • Former President of the Cell Biology Section of the National Committee of Universities,
  • Corresponding member of the French Academy of sciences since 1993 (Human Biology and Medical Sciences section).[41]
  • Member of the French Academy of Medicine 3rd Division since 2001,[42] President of the Cancer Commission of this academy (2006-2011).

International[edit]

Prices[edit]

  • 1984 - Gaston Rousseau Prize from the French Academy of sciences
  • 1988 - Joannidès Grand Prize of the French Academy of sciences
  • 1990 - Léon Baratz Prize from the French Academy of Medicine.

References[edit]

  1. ^ F. Vignon et al., « Endocrinologie. Les protéines œstrogéno-induites sécrétées par les cellules mammaires  cancéreuses humaines MCF7 stimulent leur prolifération », C. R. Acad. Sci. Paris, 296, (1983)., p. 151-156
  2. ^ D. Chalbos,et al., « Estrogens stimulate cell proliferation and induce secretory proteins in a human breast cancer cell line (T47D) », J. Clin. Endocrin. Metab., 55, (1982), p. 276-283
  3. ^ B. Westley and H Rochefort, « A secreted glycoprotein induced by estrogen in human breast cancer cell lines », Cell, 20, (1980), p. 352-362
  4. ^ M. Morisset, F. Capony, H. Rochefort, « The 52-kDa estrogen-induced protein secreted by MCF7 cells is a lysosomal acidic protease », Biochem. Biophys. Res. Commun., 138, (1986), p. 102-109
  5. ^ a b F Capony et al., « Phosphorylation, glycosylation and proteolytic activity of the 52kD estrogen-induced protein secreted by MCF7 cells », J. Cell. Biol., 104, (1987), p. 253-262
  6. ^ a b c d H. Rochefort et al., « Estrogen-induced lysosomal proteases secreted by breast cancer cells. A role in carcinogenesis ? », J. Cell Biochem., 35, (1987), p. 17-29
  7. ^ a b P. Augereau et al., « Cloning and sequencing of the 52K cathepsin D cDNA of MCF7 breast cancer cells and mapping on chromosome 11 », Mol. Endocrinol., 2, (1988)., p. 186-192
  8. ^ a b H. Rogier et al., « Two-site immuno-enzymometric assay for the 52-kDa-cathepsin D cytosols of breast cancer  tissues », Clin. Chem., 35, (1989), p. 81-85
  9. ^ a b S Thorpe, H. Rochefort et al., « Association between high concentrations of Mr 52,000 cathepsin-D and poor prognosis in primary human breast cancer », Cancer Res., 49, (1989), p. 6008-6014
  10. ^ F. Spyratos, et al., « Cathepsin D: An independent prognostic factor for metastasis of breast cancer », The Lancet, ii, 8672, (1989), p. 1115-1118
  11. ^ a b F. Capony et al., « Increased secretion and altered proces¬sing and glycosylation of pro-cathepsin D in human mammary cancer cells », Cancer Res., 49, (1989), p. 3904-3909
  12. ^ a b V. Cavailles, M. Garcia, H. Rochefort, « Regulation of cathepsin D and pS2 gene expression by growth factors in MCF7 human breast cancer cells », Mol. Endocrinol., 3, (1989), p. 552-558
  13. ^ a b c d H. Rochefort et al., « Cathepsin D in breast cancer: From molecular and cellular biology to clinical applications », Cancer Cells, (Cold Spring Harbor NY), 2, (1990), p. 383-388
  14. ^ a b M. Garcia, D. Deroccq, P. Pujol, H. Rochefort, « Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency », Oncogene, 5, (1990), p. 1809-1814
  15. ^ a b V. Cavailles, P. Augereau, and H Rochefort, « Cathepsin D gene is controlled by a mixed promoter and estrogens stimulate only TATA dependent transcription in breast cancer cells », Proc. Natl. Acad. Sci. USA, 90, (1993), p. 203-207
  16. ^ P. Roger et al., « Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors », Human Path., 3, (2000), p. 593-600
  17. ^ M Glondu et al., « Down-regulation of cathepsin D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells », Oncogene, 21, ( 2002), p. 5127-5134
  18. ^ H Rochefort et al., « How to target estrogen receptor-negative breast cancer? », Endocrine Related Cancer, 10, (2003), p. 261-266
  19. ^ A. Philips, D. Chalbos, H. Rochefort, « Estradiol increases and antiestrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells, without affecting c-fos and c-jun synthesis », J. Biol. Chem., 268, (1993), p. 14103-14108
  20. ^ G. Clinton, et al., « Estrogens increase the expression of fibulin 1, an extracellular matrix protein, secreted by human ovarian cancer cells », Proc. Natl. Acad. Sci. USA, 93, (1996), p. 316-320
  21. ^ P. Roger et al., « Increased immunostaining of fibulin-1, an estrogen-regulated protein in the stroma of human ovarian epithelial tumors », Am. J. Pathol., 153, (1998), p. 1579-1588
  22. ^ H.Rochefort, D. Chalbos, «Progestin-specific Markers in Human Cell Lines: Biological and Pharmacological Applications», Mol. Cell. Endocrinol., 36, (1984), p. 3-10
  23. ^ S. Bardon, F. Vignon, D. Chalbos, H Rochefort, « RU486, a progestin and glucocorticoid antagonist inhibits the growth of breast cancer cells via the progesterone receptor », J. clin. endocrin. metab., 60, (1985), p. 692-697
  24. ^ D. Chalbos et al., « Fatty acid synthetase and its mRNA are induced by progestin in breast cancer cells », J. biol. chem., 262, (1987), p. 9923-9926
  25. ^ D. Chalbos et al., « Expression of the progestin-induced fatty acid synthetase in benign mastopathies and breast cancer as measured by RNA in situ hybridization », J. Natl. Cancer Inst., 82, (1990), p. 602-606
  26. ^ P.Roger , J.A.Gustafson, et al., « Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary  tumors », Cancer Res., 61, (2001), p. 2537-2541
  27. ^ H. Rochefort, « Gènes induits par les estrogènes dans les cancers du sein et leur intérêt Médical », Bull Acad Natl Med., 183, (1999), p. 955-971
  28. ^ H Rochefort, « Le traitement hormonal substitutif (THS) de la ménopause ; risques et bénéfices », Bull Acad Natl Med, 186, (2002), p. 447-540
  29. ^ H Rochefort, Cl Sureau, « Traitement hormonal substitutif de la ménopause: Evolution récente du rapport Bénéfices /Risques », Bull Acad Natl Med, 187, (2003), p. 1707-1711
  30. ^ H Rochefort H, Rouëssé J, « How to reduce the incidence of breast cancer », Bull Acad Natl Med., 192 (1), (2008 jan), p. 161-79
  31. ^ H Rochefort, Balaguer P, « Endocrine disruptors: are they carcinogens? », .Bull Acad Natl Med., 194 (6), (2010 jun), p. 1159-63
  32. ^ H Rochefort, Jouannet P, « Endocrine disruptors and hormone dependant cancers. Mechanisms and proposal to reduce the risks », Bull Acad Natl Med, 195, (2011), p. 1965-79
  33. ^ H Rochefort, « Bisphenol A et Cancers hormone dependants; risque potentiel et mécanisme d’action », Médecine/Sciences, vol 29, (2013), p. 539-45
  34. ^ H Rochefort, « Hormonal carcinogenesis in women: from mechanisms to prevention », C R Biol. Acad Sciences, 331(2), (2008 feb), p. 104-13
  35. ^ H Rochefort, « Endocrine disruptors (EDs) and hormone-dependent cancers: Correlation or causal relationship? », C R Biol, vol 340, (september–october 2017), p. 439-445
  36. ^ "Les Antiœstrogènes".
  37. ^ "Hormonal control of cell cycle".
  38. ^ "Hormones et cancer du sein".
  39. ^ "Academia".
  40. ^ "Google Scholar".
  41. ^ "Académie des sciences".
  42. ^ "Académie de médecine".
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