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Antihormone induced compensatory signalling in breast cancer: an adverse event in the development of endocrine resistance

Gee, Julia Margaret Wendy, Nicholson, Robert Ian, Barrow, Denise, Dutkowski, Carol Mary, Goddard, Lindy, Jordan, Nicola J., McClelland, Richard Andrew, Knowlden, Janice Mary, Francies, Hayley E., Hiscox, Stephen Edward and Hutcheson, Iain Robert 2011. Antihormone induced compensatory signalling in breast cancer: an adverse event in the development of endocrine resistance. Hormone Molecular Biology and Clinical Investigation 5 (2) , pp. 67-77. 10.1515/HMBCI.2011.009

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Abstract

Using MCF7 breast cancer cells, it has been shown that antihormones promote expression/activity of oestrogen-repressed tyrosine kinases, notably EGFR, HER2 and Src. These inductive events confer responsiveness to targeted inhibitors (e.g., gefitinib, trastuzumab, saracatinib). We observed that these antihormone-induced phenomena are common to ER+HER2– and ER+HER2+ breast cancer models in vitro, where targeting of EGFR, HER2 or Src alongside antihormone improves antitumour response and delays/prevents endocrine resistance. Such targeted inhibitors also subvert acquired endocrine resistant cells which retain increased EGFR, HER2 and Src (e.g., TAMR and FASR models derived after 6–12 months of tamoxifen or Faslodex treatment). Thus, antihormone-induced tyrosine kinases comprise “compensatory signalling” crucial in limiting maximal initial antihormone response and subsequently driving acquired resistance in vitro. However, despite such convincing preclinical findings from our group and others, clinical trials examining equivalent antigrowth factor strategies have proved relatively disappointing. Our new studies deciphering underlying causes reveal that further antihormone-promoted events could be pivotal in vivo. Firstly, Faslodex induces HER3 and HER4 which sensitise ER+ cells to heregulin, a paracrine growth factor that overcomes endocrine response and diminishes antitumour effect of agents targeting EGFR, HER2 or Src alongside antihormone. Secondly, extended antihormone exposure (experienced by ER+ cells prior to adjuvant clinical relapse) can “reprogramme” the compensatory kinase profile in vitro, hindering candidate antigrowth factor targeting of endocrine resistance. Faslodex resistant cells maintained with this antihormone for 3 years in vitro lose EGFR/HER2 dependency, gaining alternative mitogenic/invasion kinases. Deciphering these previously unrecognised antihormone-induced events could provide superior treatments to control endocrine relapse in the clinic.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: antihormone; breast cancer; ERBB; resistance; Src
Publisher: De Gruyter
ISSN: 1868-1883
Last Modified: 28 Jun 2019 03:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/17251

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